AB0294 INFLAMMATION AND IMMUNOMODULATORY THERAPIES INFLUENCE THE RELATIONSHIP BETWEEN ATP-BINDING CASSETTE TRANSPORTER A1 (ABCA1)-MEDIATED CHOLESTEROL EFFLUX AND CORONARY ATHEROSCLEROSIS IN RHEUMATOID ARTHRITIS
Authors: G. Karpouzas, B. Papotti, S. Ormseth, M. Palumbo, E. Hernandez, M. P. Adorni, F. Zimetti, M. Budoff, N. Ronda
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Cholesterol efflux capacity (CEC) measures the ability of high-density lipoprotein (HDL) to remove cholesterol from atherosclerotic plaques. It is mediated by various membrane transporters exporting cholesterol to HDL particles based on their maturation. It is unclear whether CEC associates with coronary atherosclerosis independently of HDL-C levels in RA or whether CEC itself or its impact on atherogenesis are influenced by inflammation or RA-specific therapies. Conventional and biologic DMARDs are atheroprotective while corticosteroids are proatherogenic. ATP-binding-cassette membrane transporter A1 (ABCA1) exports cholesterol to apo A1 or lipid-poor HDL particles. <h3>Objectives</h3> We here explored associations between ABCA1 CEC and coronary atherosclerosis and whether inflammation and disease-specific therapies influence this relationship. <h3>Methods</h3> Coronary atherosclerosis (noncalcified, partially or fully calcified plaque and coronary artery calcium [CAC] score) was evaluated with computed tomography angiography in 140 patients without cardiovascular disease and reassessed in 99 after 6.9±0.4 years. ABCA1 CEC was measured in J774 macrophages as previously described. Multivariable negative binomial regression evaluated associations of ABCA1 CEC with plaque numbers at baseline and follow-up. Robust logistic regression tested the association of ABCA1 CEC with CAC progression (&gt;2.5 U difference in square root CAC scores). <h3>Results</h3> ABCA1 CEC was not associated with baseline atherosclerosis. Inflammation, prednisone, methotrexate or bDMARD use did not influence the relationship between ABCA1 CEC and baseline plaque. However, both baseline and cumulative inflammation modulated the relationship between ABCA1 CEC and plaque progression. Each standard deviation (SD) increase in ABCA1-CEC associated with 41% fewer new plaques in patients with low (&lt;median) baseline ESR but 67% more new plaques in those with high (&gt;median) ESR (p for interaction = 0.015, Figure 1). Likewise, each SD increase in ABCA1 CEC associated with 53% fewer new calcified plaques in patients with low (&lt;median) but not high (&gt;median) time-averaged CRP (p for interaction = 0.028). Higher ABCA1 CEC (per SD) associated with 37% fewer new calcified plaques in baseline prednisone nonusers but not users (p for interaction = 0.021). For time-weighted mean daily prednisone dose, each SD increase in ABCA1 associated with 31% fewer new plaques in unexposed patients (p for interaction vs. high exposure group = 0.034), as well as 53% fewer and 2.4 times more new calcified plaques in the unexposed and high exposure groups respectively (p for interaction unexposed vs. high exposure = 0.004). Higher ABCA1 CEC (per SD) was linked to 2.2 times higher adjusted likelihood of CAC progression in methotrexate nonusers but not in users (p for interaction = 0.018). Likewise, each SD increase in ABCA1 CEC associated with 2.7 times more new plaques in baseline bDMARD nonusers and 35% fewer new plaques in users (p for interaction ≤ 0.001). <h3>Conclusion</h3> ABCA1 CEC attenuated plaque progression exclusively in patients with low baseline and cumulative inflammation as well as in baseline methotrexate and bDMARD recipients. In contrast, ABCA1 CEC associated with plaque progression in baseline corticosteroid recipients and those receiving high time-weighted daily average prednisone dose during follow-up. In uncontrolled or inadequately treated disease ABCA1 CEC fails to counteract and may in fact contribute to the proatherogenic state promoted by inflammation and oxidation. The latter also occurs during treatment with prednisone, known to promote intracellular cholesterol accumulation. When RA is sufficiently treated and controlled, ABCA CEC effectively performs its atheroprotective function. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> George Karpouzas Speakers bureau: Sanofi/ Genzyme/ Regeneron, BMS, Consultant of: Sanofi/ Genzyme/ Regeneron, Janssen, Scipher, Grant/research support from: Pfizer, Bianca Papotti: None declared, Sarah Ormseth: None declared, Marcella Palumbo: None declared, Elizabeth Hernandez: None declared, Maria Pia Adorni: None declared, Francesca Zimetti: None declared, Matthew Budoff: None declared, Nicoletta Ronda: None declared.